Currently there are a number of biomedical applications where there is a need to rapidly and thoroughly mix two or more components in the operating room substantially immediately prior to administration to the patient. The mixing of components can typically involve extraction of one component in fluid form from a vial or other container and transfer of such component into a separate container which holds another component. In particular instances, only a portion of the contents of a vial or container is to be utilized for preparing a mixture prior to administering. Accordingly, the extraction and transfer can involve precise measuring of one or more components to be mixed.
A variety of problems may occur when utilizing conventional methodology and devices for mixing and/or administering biomedical agents to an individual. For example, where multiple components are to be mixed, extraction and transfer of one component and introduction of such component into another component can potentially expose one or both of the components to a non-sterile or contaminated environment leading to contamination of the resulting mixture. Additionally, incomplete extraction or improper measurement of one or more components can result in preparation and/or administration of an improper dosage. In particular instances, once biomedical agents are mixed the mixture must again be extracted from a vial or container into a syringe prior to administering to an individual. Such additional transfer can lead to additional opportunities for contamination, incomplete extraction of contents and/or inaccurate measuring of a component or the resulting biomedical agent. In practice, there is limited availability of sterile environments for maintaining sterility during transfer and/or mixing of components, or preparation and transfer of biomedical agents. Additional errors can result from use of the wrong diluent to reconstitute the medication. Finally, preparation of biomedical agents utilizing multiple components can be tedious and time consuming due to factors such as the need to access individually packaged items such as separate vials and/or transfer devices, or to measure one or more components to be combined to form the biomedical agent. The multiple packaging and storage containers such as separate vials and/or transfer devices increase the cost of care and also create an additional waste stream which has to be dealt with in accordance with regulations governing the disposal of biomedical waste. There is a need in a simplified system for segregated storage and rapid and thorough mixing of two or more components in the operating room substantially immediately prior to administration to the patient, which can also reduce the risk of contamination during preparation.
Preparation of injectable drugs or hemostatic agents often requires a thorough mixing of two or more components which are stored in separate compartments. Use of multiple vials and syringes is expensive and wasteful, complicates the preparation, increases the probability of error, and requires proper disposal of used containers. For example, in preparation of a hemostatic paste based on biopolymer, such as gelatin, in mixture with thrombin, the surgeon often performs the mixing by using two interconnected connected syringes and moving the paste back and forth to mix gelatin with saline solution containing thrombin. One syringe is then discarded.
In preparation of reconstituted solution of a protein, such as reconstituted thrombin or fibrinogen from lyophilized thrombin or fibrinogen, the dry lyophilized powders need to be thoroughly mixed when reconstituted with water or saline.
In some commercially available hemostatic kits, reconstitution of lyophilized thrombin is performed in a vial into which water is injected from a syringe. After swirling the mixture, the solution is aspirated back into syringe. The reconstitution of the thrombin can be slow because there is no forced mixing in the vial. Then the solution is expressed into a sterile cup and the syringe and the vial are discarded. The solution is then aspirated by another syringe can be connected via a luer to the syringe containing the gelatin matrix. The contents are then mixed by moving between syringes back and forth, after which one syringe is discarded and the ready mixture is expressed from the last syringe. The process of using and discarding a vial, a cup, and two syringes to prepare one syringe with the hemostatic paste in multiple sequential steps requires time and high attentiveness of the healthcare professional.
There are a number of known multi-chamber, single barrel as well as multi-barrel syringes which attempt to accomplish the segregated storage of two components and subsequent mixing and expression of the resulting mixture from the syringe.
A number of references are utilizing an intermediate free piston or stopper in front of the plunger separating the two sub-compartments and a bypass channel or groove in the sidewall of the syringe barrel.
Other references describe the plunger separating front compartment and back compartment in the barrel of the syringe, with a one way valve in the plunger enabling mixing of the materials in the two compartments.
Other references disclose a secondary barrel coaxially located within the first barrel, wherein the second barrel might be used as a plunger or plunger stem.
Other references disclose two syringes which are interconnected and used for mixing components by moving from the mix from one syringe to another.
None of the references provide, in a single syringe, for the capability of vigorous back and forth mixing between the compartments and thus for rapid effective reconstitution and/or mixing of separately stored components. The known systems utilizing valves are complex and can plug up with the mixing materials, or can leak during storage. Only uni-directional movement of the plunger (i.e. forward) is possible, resulting in insufficiently efficient mixing of the components.
U.S. Pat. No. 6,817,987 titled “Mixing Hypodermic Syringe” discloses a syringe holding both a solvent and a soluble component having a tubular body with a bypass, a plunger axially slidable in the tubular body, and a stem projecting axially rearward out of the body from the plunger. A cover fits over the front end of the tubular body and is so tight that the front compartment can be pressurized to a superatmospheric pressure without leakage out the front end. A free piston slidable in the tubular body forward of the plunger subdivides the body forward of the plunger into a front compartment at the front body end holding the soluble component and a rear compartment between the plunger and the piston and holding the solvent. Stops are provided for arresting the free piston when it is level with the bypass in a position permitting flow through the bypass between the compartments.
U.S. Pat. No. 5,080,649 titled “Dual-Compartment Hypodermic Syringe” discloses a hypodermic syringe that has an elongated tubular body having a front end adapted to carry a needle, a rear end, and a bypass between the ends. A front partition piston defines with the front end a front compartment that is adapted to hold a substance and a rear piston defines with the front partition piston a rear compartment adapted to hold a fluid miscible with the front-compartment substance. The front partition piston is displaceable into a middle position in the bypass for fluid communication between the compartments. A stem projecting rearward out of the body from the rear piston is provided with axially spaced front and rear external screwthreads and has a clear region between the screwthreads. A damper on the rear end of the body can engage the screwthreads for slowing axial movement of the screwthreads past the rear end of the body and for permitting relatively rapid axial movement of the stem in the body when the clear region is level with the damper.
U.S. Pat. No. 6,419,656 titled “Medical Syringe with Braked Step-Advance Plunger” discloses a medical syringe that has a tubular body extending along an axis and having a front end and a rear end, a plunger axially slidable in the body and carrying a stem projecting axially rearward out of the body from the plunger, and a free piston slidable in the body forward of the plunger and subdividing the body forward of the plunger into a front compartment at the front body end and a rear compartment between the plunger and the piston. The body is formed with a bypass passage forward of the piston in a starting position so the front compartment can hold a soluble medicament and the rear compartment can hold its solvent. Structure at the rear body end forms a radially inwardly open angularly limited cutout and at least two axially spaced, angularly offset, and radially outwardly projecting stop bumps on the stem are axially displaceable through the cutout in respective angularly offset positions of the stem. The stop bumps are axially engageable against the structure except when the stem is in the respective angular position. An elastically deformable brake element engaged between the body and the stem for axially slowing axial forward advance of the stem.
U.S. Pat. No. 5,817,056 titled “Prefilled Syringe” discloses a prefilled syringe capable of separate storage of different substances before use. It includes a tubular body having an injection needle at one end and a plunger at the other end, and a partition slidable axially in the tubular body. The partition includes a front part and a rear part independent of each other, and as a whole dividing the interior space of the tubular body into a front compartment and a rear compartment in a sealing manner for storing mutually different substances. A bypass is disposed generally between the front and rear compartments to introduce the substance in the rear compartment into the front compartment when the partition is slid under pressure provided by the plunger to be adjacent to the bypass to thereby mix the substances immediately prior to injection.
U.S. Pat. No. 5,364,350 titled “Twin-Chamber Syringe Filled with a Charge of Activity-Sensitive Human Protein” discloses a twin-chamber syringe that has a pyrogen-free sterile solvent in the chamber averted from the needle, and in the second chamber facing the needle a charge of activity-sensitive human protein, introduced and lyophilized in a single operation in the syringe, where it is stored, in a quantity necessary for therapeutically effective administration. The invention also relates to the filling of the syringe and the potential it offers for immediate use of activity-sensitive human proteins and for self-administration at home.
U.S. Pat. No. 5,899,881 titled “Stopper Assembly Having Bypass Features for Use in a Multi-Chamber Syringe Barrel” discloses a stopper assembly having by-pass features for use in a multi-chamber syringe barrel. The stopper assembly includes a sequential stopper body responsive to fluid forces for enabling the sequential delivery of disparate contents, such as disparate fluids, separately held in the syringe barrel. The sequential stopper body has a generally cylindrical sidewall with a distal end, a proximal end and a longitudinal axis therethrough. The stopper assembly also includes a generally cylindrical flow channelizer mounted to the distal end of the sequential stopper body. The flow channelizer enables the reconstitution of dry medicament held in the syringe barrel distally of the flow channelizer. The flow channelizer features opposed proximal and distal ends and a generally cylindrical outer surface therebetween. At least one fluid flow channel extends between the proximal and distal ends of a flow channelizer. A distally directed, conically-shaped projection is located at the distal end of the flow channelizer to prevent the accumulation of dead space between the channelizer and the internal shoulder located at the distal end of the syringe barrel. The stopper assembly may be employed in a multi-chambered syringe barrel featuring a by-pass channel to permit fluids to pass distally of the stopper assembly. The multi-barreled syringe barrel can be separated into disparate chambers by one or more by-pass stoppers so as to contain disparate components intended for sequential delivery by the stopper assembly.
U.S. Pat. No. 7,021,561 titled “Spray Device and Method” discloses a spray device including a barrel having a bypass and at least two spaced stoppers defining a first and second chambers and a spray nozzle. Movement of the first stopper drives the second stopper to the bypass and the fluid in the first chamber into the second chamber, mixing the fluid and substance. Continued movement of the first and second stoppers drives the mixture through the spray nozzle. The spray device may include a third stopper having a body in the tubular barrel which is moved toward the spray nozzle. The movement of the third stopper provides space for the mixture and prevents unpressurized fluid from flowing through the spray nozzle. The third stopper includes an axial stalk. The stalk may be deformable or the stalk may be separate from the body and the spray nozzle includes a longitudinal internal passage which provides communication with the spray port.
U.S. Pat. No. 4,036,225 titled “Bicompartmental Syringe” discloses a syringe for use in the distribution, conditioning and injection of two or more products to be mixed just before use, characterized in that it comprises two separate and contiguous compartments A and B, resulting from the assembly of two complimentary, joinable receptacles.
U.S. Pat. No. 4,613,326 titled “Two-Component Medication Syringe Assembly” discloses a two-component syringe assembly which includes an elongate barrel having a chamber for retaining fluid and a distal end having a passageway therethrough communicating with the chamber. A bypass stopper is slidably positioned in fluid-tight engagement inside the barrel. The barrel also includes a bypass defining a bypass zone positioned along the barrel for allowing fluid to flow around the bypass stopper when the bypass stopper is positioned intermediate the ends of the barrel in the bypass zone. A stopper is slidably positioned in fluid-tight engagement inside the barrel. A rigid plunger rod having an elongate body portion engages the stopper to facilitate its operation. A barrier flange is positioned on the body portion and intermediate the ends thereof. The barrier flange projects outwardly from the body portion into the space between the inside wall of the barrel and the outside of the body portion for acting as a barrier for blocking the path of fluid which may be propelled in a distal direction through the bypass when the syringe is being operated. The area described by the barrier flange as viewed along the longitudinal axis of the plunger rod is at least about 87 percent as large as the area described by the interior of the barrel as viewed along the longitudinal axis of the barrel.
PCT Publication No. WO2006/003653 titled “A Syringe Assembly” discloses a syringe assembly that consists of two basic types of assembly units: a dispensing unit, and a separate, independent plunger unit. The dispensing unit and the plunger unit are assembled together coaxially to form a two-unit syringe assembly for storage or prior to use. At least the dispensing unit is a container for a material to be dispensed and, by inserting one or more extension units between the dispensing unit and the plunger unit, additional compartments may be added. Each extension unit may contain a different component of a formulation in any predetermined quantity. The syringe assembly allows the user to store one or more components of a formulation in separate individual units that can be assembled easily into a single multi-compartment syringe assembly, which can store the multiple components separately until they are ready for use, at which time the components may be mixed to form the formulation.
U.S. Pat. No. 4,424,057 titled “Wet-Dry Syringe” discloses a wet-dry syringe for combining and mixing a liquid and a solid medicament or at least two dissimilar liquid medicaments prior to the application thereof to a patient includes a first vial having liquid or solid medicament disposed between a pair of identical vial seals. A second vial functions as a piston rod and includes a pair of end seals with a liquid medicament disposed therein. One of the second vial seals includes a hollow piercing needle which when utilized to pierce one end seal of the first vial causes the medicament therein to flow into the first vial thereby mixing the medicaments prior to application to a patient by means of a needle piercing assembly which pierces the second of the first vial seals and the patient to which the mixed medicaments are to be infused. The second vial functions as a piston rod and aides in the discharge of the medicaments.
U.S. Pat. No. 5,704,918 titled “Syringe” discloses that in medical scenes requiring emergency, where plural medicines are to be injected simultaneously, or solution of solid medicine is to be injected, different kinds of injection agents, without being previously mixed, are accommodated in chambers formed separately in a cylinder. In using a syringe, both injection agents can be sequentially injected separately or together by a simple operation.
U.S. Pat. No. 7,731,678 titled “Syringe Devices and Methods for Mixing and Administering Medication” discloses a device having a chamber within a syringe. A fluid passageway extends through a syringe piston. A valve is associated with the passageway controlling fluid passage through the piston. The invention includes a piercing structure having a head segment and a body portion, with a channel through the body portion and through at least one surface of the head without passing through the tip. In another aspect the invention encompasses a method of preparing an agent for administration to an individual. A first component is provided within a syringe and a second component is provided within a vial. A closed valve is associated with a fluid passageway between the vial and the syringe barrel through a piston. Valve repositioning allows fluid passage and sliding of the piston joins the first and second components. Repeated sliding of the piston mixes the components to produce the medication agent.
PCT Publication No. WO 2003/084840 titled “Device for Dispensing a Fluid Product” discloses a device for dispensing a fluid product containing two separate fluid or powdery products which are mixed before being dispensed. Said device comprises a first reservoir containing a first fluid or powdery product, a second reservoir containing a second fluid or powdery product, a mixing system, and a dispensing system. The inventive device is characterized by the fact that the mixing system is provided with a piston which separates the first and second reservoirs and comprises one-directional valve means which release the product that is contained in the first reservoir towards the second reservoir and prevent the product that is contained in the second reservoir from flowing towards the first reservoir. Said separating piston is movable so as to increase the volume of the second reservoir when the mixing system transfers the first product contained in the first reservoir into the second reservoir, preventing any relief in the second reservoir during mixing.
U.S. Pat. No. 3,511,239 titled “Multi-Chamber Syringe” discloses a syringe, which comprises a vial cylinder and a piston axially movable in the vial cylinder and dividing the vial cylinder into at least two separate chambers. The piston has means permitting liquid movement from a front to a rear chamber but blocking movement of said liquid in the opposite direction. A piston rod is non-movably secured to and displaces the piston, which is movable in the vial cylinder towards the injection end thereof. At least one stopper has a central bore and is disposed in and seals the vial cylinder, permitting independent and free movement of the piston during its forward movement, and the piston rod projects through and is guided by the stopper.
U.S. Pat. No. 3,662,753 titled “Syringe” discloses a syringe assembly enabling mixed discharge of substances retained in separated condition until intended use, employing a plunger and barrel arrangement that retains the substances separated during storage, allows mixing thereof prior to discharge, and causes discharge of the mixed substances. The plunger head has a diagonally oriented peripheral seal lip, preferably cooperative with differing diameter barrel portions.
European Patent publication No. 242,956 titled “Self-Contained Material Mixing Apparatus” discloses a self-contained material mixing apparatus that is useful for mixing two substances separately contained in the apparatus. The apparatus is embodied as a syringe having a piston therein separating two compartments within the syringe body. The piston causes an incompressible substance in the rearward compartment to pass to the forward compartment when the volume of the rearward compartment is reduced, but precludes passage of substances in the forward compartment to the rearward compartment. The substances to be ultimately mixed together are separately placed in the compartments, which substances can be, for example, a drug and a diluent. For mixing of the substances, the piston is moved rearwardly in the syringe and to produce an incompressible material in the rearward compartment that is forced to the front compartment through the one-way valve provided by the piston. After mixing of the substances in the forward compartment, the material is discharged from the syringe to a patient by moving the piston forwardly in the syringe to expel the mixture from the syringe through an outlet nozzle located at the front of the syringe.
U.S. Pat. No. 3,766,917 titled “Two Compartment Ampul Syringe” discloses a two-chamber syringe with an ampoule cylinder which at one end runs into a mouthpiece, designed to take an injection needle and which is as a rule closed in the first place, with at the end of the ampoule cylinder opposite the mouthpiece an elastic closure piston which seals against the exterior, and with a separating piston which divides the ampoule cylinder into two chambers, and with at least one pusher element acting on the separating piston, characterized in that the separating piston and/or an associated pusher element, passing through the separating piston and displaceable, has or forms a connection channel bridging over the separating piston, which channel prior to use of the syringe ampoule is closed, and can be opened by an axial movement of the pusher element relatively to the separating piston, and in that both pistons are made displaceable, and during the injection can be connected together so as to be displaceable in common.
PCT Publication No. WO 2008/150208 titled “A Substance Dispensing Device and a Filling Instrument for such a Device” discloses a device for storing, mixing and dosing of substances, typically used as a syringe. The device comprises a cylinder with a spout, an end piston and at least one mixing piston. At least a first and a second cylinder volume separated by the mixing piston are formed, The mixing piston is provided with a valve device which, when open, allows substance to be exchanged between said first and second cylinder volumes, and where the mixing piston is slideable with respect to the end piston for mixing of substances between the first and second cylinder volumes. Such a device may store two or more substances completely sealed and separate from each other. The device further allows mixing of selected substances inside a sterile device that may be used as a syringe. Finally, the same device also allows sequential dispensing of substances, or mixes of substances. The invention further relates to a filling instrument for such a device for storing, mixing and dosing of substances.
U.S. Pat. No. 5,785,683 titled “Disposable Syringe with Two Variable Volume Chambers” discloses a pre-filled disposable syringe to be used in the administration of powdered drug diluted at the time of injection.
U.S. Patent Publication No. 2011/0155620 titled “Rapid Reconstitution for Lyophilized Pharmaceutical Suspensions” discloses a method of preparing and reconstituting a sterile, lyophilized pharmaceutical active for rapid reconstitution by evacuating a lyophilized pharmaceutical active-containing container until the pressure within the container is less than about 300 Torr and hermetically sealing the evacuated container. The sterile, lyophilized pharmaceutical active can be prepared by flash freezing a pharmaceutical active-containing composition then lyophilizing the composition. The hermetically sealed lyophilized pharmaceutical active can be reconstituted by adding at least the total volume of liquid necessary for reconstitution of the sterile, lyophilized pharmaceutical active to the sterile, lyophilized pharmaceutical active, sealed under a pressure of less than about 300 Torr, in less than about 10 seconds to yield, within about 5 minutes, an administrable pharmaceutical active-containing composition. One aspect of the herein described sterile, lyophilized pharmaceutical active is a packaged sterile pharmaceutical active comprising an evacuated, hermetically sealed container having disposed therein a sterile, lyophilized pharmaceutical active, sealed under a pressure of less than about 300 Torr.
None of the references provide, in a single syringe, for the capability of vigorous back and forth mixing between the compartments and thus for rapid effective reconstitution and mixing of segregatedly stored components. The known systems utilizing valves are complex and can plug up with the mixing materials, or can leak during storage. Only uni-directional movement of the plunger (i.e. forward) is possible, resulting in insufficiently efficient mixing of the components. It would be desirable to develop alternative multi-compartment medical devices for segregated storage and on demand mixing of at least two components and for expressing the resulting mixture from the device for use in treating a patient.